Process for the oxidation of 20-hydroxy-pregnanes



United States Patent Ofiice 3,056,779 Patented Get. 2, 1962 3,056,779PROCESS FOR THE OXIDATION OF ZO-HYDROXY-PREGNANES Albert Wettstein,Riehen, and Georg Antler, Karl Heusler, and Peter Wieland, Basel,Switzerland, assignors to Ciha Corporation, a corporation of Delaware NoDrawing. Filed Feb. 16, 1961, Ser. No. 89,638 Claims priority,application Switzerland Feb. 18, 1960 2 Claims. (Cl. 260239.57)

The present invention relates to a process for the oxidation of20-hydroxy pregnanes, more especially a process for the oxidation of18:11-lactones of 11,8:20-dihydroxypregnane-lS-acids which may contain aketalized oxo group in the 3-position.

20-hydroxy-pregnanes are, as a rule, readily oxidizable to 20'ketoneswith various oxidizing agents in acid or also in weakly alkalinesolution, particularly with compounds of hexavalent chromium in glacialacetic acid or with a pyridine chromate complex. It has been observed,however, that in 18:11-lactones of 11,8:20-dihydroxy-pregnane-lS-acidsthe ZO-hydroxy group can only be oxidized with difiiculty by pyridinechromate both in an anhydrous and in an aqueous solution, since it isevident that the hydroxyl group and the lactone group influence eachother, slowing down oxidation and even partially preventing it. Inattempts to oxidize 18:11-1actones of 115:20-dihydroxy-pregnane-lS-acids in several cases of oxidation with pyridinechromic acid, even with a long reaction time and at a temperature up to40 C., oxidation to the 20- ketone was always incomplete. In some casesoxidation did not take place at .all.

It has now been found that 18:11-lactones of saturated or unsaturated11B:20-dihydroxy-pregnane-18-acids can be oxidized easily and inexcellent yield to form the corresponding ZO-ketones when oxidation iscarried out with a compound of hexavalent chromium in acidic solution.

It has been surprisingly found that oxidation can even be carried out inthe presence of a ketal group in acidic solution without the ketal groupbeing split. This is surprising considering the known susceptibility ofketals to acids. It is especially important to retain a ketal group,when, starting from a resulting 20-ketone, other reactions must also becarried out in which free keto groups, for example in the 3-position,interfere, for example, in the reaction for the introduction of a21-oxygen function and the like.

The oxidation according to the present process takes an especially rapidcourse and gives a good yield when the reaction is performed in acetonesolution with chromic acid-sulfuric acid at a low temperature, that isto say advantageously between 20 and +10 C. The excess mineral acid ispreferably neutralized before working up by the addition of sodium orpotassium acetate. The oxidation of the ketal-lactones may also becarried out in glacial acetic acid with chromium trioxide when a largerquantity of sodium acetate or potassium acetate is added.

The 20-hydroxy-lactones used as starting material can be prepared, forexample, according to a known process from ll-oxygenated18:20-oxido-pregnaues by acylolytic cleavage to18:20-di-acyloxy'pregnanes, hydrolysis and oxidation to 18:20-lactonesof ll-oxo-ZU-hydroxy-pregnane-l8-acids. The latter yield on reductionwith sodium borohydride with translactonization the 18:11-lactones of115220 dihydroxy pregnane 18 acids. The 18:20-lactones ofZO-hydroxy-ll-oxo-pregnane-lS-acids are also obtainable by anotherprocess which is described in US. patent application Ser. No. 74,486,filed Decemher 8, 1960, by Charles Meystre et al., in US. patentapplication Ser. No. 74,487, filed December 8, 1960, by Charles Meystreet a1. and in US. patent application Ser.

No. 74,470, filed December 8, 1960 by Oskar Jeger et al. The latterprocess consists in reacting lead tetraacetate with IS-unsubstituted20-hydroxy-pregnanes in the presence of iodine, oxidizing the resultingproducts with chromium trioxide in the presence of silver chromate and,if desired, liberating an esterified Ila-hydroxyl group by hydrolysis orintroducing a free hydroxyl group by microbiological oxidation andoxidizing any free lloc-hYdIOXYl group present to the oxo group.

The starting materials may contain further substituents in the ringsystem, particularly in one or more of the positions 1, 2, 3, 4, 5, 6,7, 8, 9, 10, 14, 15, 16, 17 or 21, such as esterified hydroxyl groups,or free or ketalized oxo groups, alkyl, such as methyl groups or halogenatoms. They may also contain double bonds, for example starting fromcarbon atom 5. Especially important starting materials are the18:20-lactones of 9a-halogen- 11,8:20/3-dihydroxy-pregnane-l8-acids thepreparation of which consists in reacting an 18:20-lactone of a 9:11;?-oxido-ZO-hydroxy-pregnane-1S-acid with a hydrohalic acid, or reacting an18:20-lactone of A -20-hydroxypregnene-18-acid with a hypohalous acid.The soobtained compounds yield the 18:11-lactones of 11:20-dihydroxy-9e-halogen-pregnane-18-acids after oxidation of thell-hydroxyl group to an oxo group and reduction with sodium borohydridewith translactonisation.

The 18:11-lactones of 1lfl-hydroxy-20-oxo-pregnane- 18-acids obtained asendproducts are important intermediates for the preparation of18-0xygenated corticoids of the type of aldosterone or9a-halogen-aldosterone.

The following examples illustrate the invention:

Example 1 225 mg. of sodium dichromate and 900 mg. of crystalline sodiumacetate are dissolved in 4.5 ml. of glacial acetic acid and 0.45 ml. ofWater. To this solution there are added 160 mg. of the 18:11-1actone ofA -3-ethylenedioxy- 11 3:ZOB-dihydroxy-pregnene-18-acid and the whole isstirred for 4 days at 20-25 C. The dark solution is then poured into 100ml. of ice-water and extracted several times with methylene chloride.The extracts are washed with sodium bicarbonate solution and with water,dried and evaporated. There are obtained 122 mg. of a crystallineresidue which contains, in addition to a little starting material and alittle of the 18:1l-1actone of M8 :20-dioxo-1lp-hydroxy-pregnene-lS-acid, as main product the 18:11- lactone of A-3-ethylenedioxy-1 1fl-hydroxy-20-oxo preg nene-l S-acid. Afterchromatography on 12 grams of silica gel there are obtained mg. of thelatter compound melting at 239.5240.5 C. from the fractions eluted froma mixture of benzene and ethyl acetate (9: 1).

Example 2 1.0 gram of the 18:11-lactone of A -3-ethylenedioxy-11,8:ZOB-dihydroxy-pregnene-l8-acid is dissolved in 25 ml. of acetone.The solution is cooled to -10 C. and there is added with vigorousstirring 1.25 ml. of a solution of 13.3 grams of chromium trioxide and11.5 ml. of concentrated sulfuric acid diluted with Water to make up50.0 ml. After 10 minutes the reaction mixture is poured into ml. of anaqueoue sodium acetate solution of 10% strength, the crystallineprecipitate is filtered off and washed well with Water. After drying,there are obtained 904 mg. of the pure 18:11-lactone of A-3-ethylenedioxy- 11,B-hydroxy-ZO-oxoapregnene 18 acid melting at 232-236 C.

Example 3 In an analogous manner to that described in Example 2 thereare obtained from 273 mg. of the 18:11-1actone of A-3-ethylenedioxy-9e-bromo-1lBzZOfi dihydroxy pregnene-18-acid 231 mg. ofthe pure 18:11-1actone of A -3- 6 ethylenedioxy-9a-bromo-1lfi-hydroxy-ZOoxo pregnene- 18-acid.

The bromlactone used as starting material is prepared as follows:

240 mg. of the 18:20-lactone of A-3-oxo11a:20;3-dihydroxy-pregnene-18-acid are dissolved in 3 ml. ofmethylene chloride and after adding 1.0 ml. of pyridine and 300 mg. ofpara-toluene-sulfonic acid chloride the whole is allowed to stand for 3days at room temperature. The reaction mixture is then diluted withmethylene chloride, washed with dilute sulfuric acid and with water. Bycrystallization of the residue of the methylene chloride solution from amixture of methylene chloride and ether there are obtained 255 mg. ofthe 18:20-lactone of A -3-oxo-11atosyloxy 205 hydroxy vpregnene 18 acidmelting at 142144 C. (with decomposition); optical rotation [a] =+48 (inchloroform); absorption maximum in ultraviolet spectrum at 229 mn(e=24,800); infrared bands at 5.69 1. ('y-lactone); 5.96 and 6.17 (A-3-ketone); 6.24 844 and 854 (tosylate).

170 mg. of the 18:20-lactone of A -3-oxo-1lu-tosyloxy-20fi-hydroxy-pregnene-l8-acid are stirred in ml. of a solution oflithium chloride in dimethylformamide of strength for 4 hours at 100 C.under nitrogen.

The reaction mixture is poured into 50 ml. of water, the solidprecipitate is suctioned OH and washed well with water. There areobtained 120 mg. of the 18:20-lactone of A -3oxo-ZOfl-hydroxypregnadiene18 acid which after crystallization from a mixture of methylene chlorideand ether and sublimation at 180 C. under 0.05 mm. pressure of mercurymelts at 205210 C.; optical rotation [M -+16 (in chloroform);ultraviolet spectrum maximum at 239 m 16,850); infrared bands at 5.68(5-ring lactone); 5.98 and 6.17; (A -3-ketone); further bands at 7.428.15 8.68 9.10p. and 9.85

500 mg. of the 18:20-lactone of n-3-oxo-20fl-hydroxy-pregnadiene-1S-acid are dissolved in 10 ml. of puredioxane, and the solution is treated with 300 mg. of N- bromosuccinimideand 1 ml. of perchloric acid of 10% strength after the addition of 2 ml.of water. The reaction mixture is stirred for minutes at roomtemperature, the excess hypobromous acid is destroyed by the addition ofsodium sulfite solution and the mixture poured into 75 ml. of ice-water.The resulting precipitate is taken up in methylene chloride, thesolution dried and evaporated. The residue consists of the crude18:1l-lactone of A -3- oxo-9a-bromo-1 15:20fi-dihydroxy-pregnene-18-acidwhich is purified by chromatography on silica gel.

By ketalization of the 18:11-lactone of A-3-oxo-9otbromo-l1,8:B-dihydroxy-pregnene-18-acid with ethylene glycoland para-toluene-sulfonic acid in benzene there is obtained the18:1l-lactone of A-3-ethylenedioxy-9ubromo-l1B:20B-dihydroxy-pregnene-l8 acid used aboveas starting material.

Example 4 970 mg. of the 18: ll-lactone of A-3ethylenedioxy-9afluoro-l1,8:20fl-dihydroxy-pregnene-18-acid aredissolved in ml. of acetone. The solution is cooled to 5 C. and thereare then added with stirring 1.15 ml. of a chromic acid-sulfuric acidsolution described in Example 2 and the whole is stirred for 20 minutesat a temperature of 5 to 0 C. 100 ml. of a sodium acetate solution of10% strength are added and the solution is extracted several times withmethylene chloride. The crude product obtained from the methylenechloride extracts is purified by chromatography on silica gel. From thefractions eluted with a mixture of benzene and ethyl acetate there isobtained by crystallization from a mixture of ether and methylenechloride the pure 18:1l-lactone of A-3-ethylenedioxy-9a-fluoro-l1fl-hydr0xy-20-oxo pregnene 18- acid.

The fluorolactone used as starting material is prepared as follows:

250 mg. of the 18:20-lactone of A -3-ethylenedioxy-9:11,8-oxido-20,8-hydroxy-pregnene-18-acid are dissolved in 1.5 ml. ofmethylene chloride and slowly added to a mixture cooled to --60 C. of10.3 ml. of tetrahydrofuran, 3.6 ml. of methylene chloride and 5.0 ml.of anhydrous hydrofluoric acid. When the addition is complete, the wholeis allowed to stand for 15 minutes at --60 C., then for 3 hours at 0 C.and then poured into a cold solution of sodium bicarbonate. The mixtureis then extracted with methylene chloride, the extracts are washed withwater, dried and evaporated. The residue (240 mg.) is filtered through12 grams of silica gel. The 18:11-l-act0ne of A-3-oxo-9u-fiuoro-1lflz20fi-dihydroxypregnene-18-acid is eluted with amixture of benzene and ethyl acetate, and with ethyl acetate.

105 mg. of this compound are dissolved in 2 ml. of glacial acetic acidand after the addition of 200 mg. of chromium trioxide in 0.5 ml. ofwater the whole is allowed to stand for 5 hours at 25 C. Working up inthe ordinary manner yields a crude product which, when crystallized frommethylene chloride and ether, yields the pure 18:1l-lactone of A-3:2O-dioxo-9v-fluoro-1lp-hydroxy-pregnene-l 8-acid.

285 mg. of the 18:11-lactone of A -3-oxo-9ot-fluoro-11B:20fl-dihydroxy-pregnene-l8-acid are dissolved in ml. of benzene and,after the addition of a solution of 20 mg. of pana-toluene-sulfonic acidin 10 ml. of ethylene glycol, boiled for 6 hours under reflux using awaterseparator. The mixture is cooled, 20 ml. of saturated sodiumbicarbonate solution are added with stirring, and the solution dilutedwith 50 ml. of benzene. The organic solution is separated, washed withwater, dried and evaporated in a water-jet vacuum. There are obtained290 mg. of crude 18:11-lactone of A-3-ethylenedioxy-9ufiuoro-l1B:ZOfl-dihydroxy-pregnene-l8-acid which isoxidized directly as described above.

When instead of anhydrous hydrofluoric acid a solution of hydrogenchloride in methanol is used for the cleavage, the 18:11-lactone of A-3-oxo-9a-chloro-1lfi:20fi-dihydroxy-pregnene-18-acid is obtained which,as described above for the 9-fiuoro-compound, is converted into the 18 1l-lactone of A -3ethylenedioxy-9a-chlor0-l lfB-hydroxy-20-oXo-pregnene-1 S-acid.

What is claimed is:

1. Process for the manufacture of a member selected from the groupconsisting of 3-ketals of '18:11-lactones of11hydroxy-3,20-dioxo-pregnane-18=acids and the corresponding compoundshaving a double bond in the S-position, which comprises oxidizing amember selected from the group consisting of 3-ketals of 18:11-lactonesof 11, 20-dihydroxy-3oxo-pregnane-18-acids and the correspondingcompounds having a double bond in the 5- position with a compound ofhexavalent chromium in acid solution;

2. Process as claimed in claim 1, wherein the oxidation is carried outwith chromium trioxide and sulfuric acid in acetone.

2,959,586 Kerwin et al. Nov. 8, 1960

1. PROCESS FOR THE MANUFACTURE OF A MEMBER SELECTED FROM THE GROUPCONSISTING OF 3-KETALS OF 18:11-LACTONES OF11-HYDROXY-3,20-DIOXO-PREGNANE-18-ACIDS AND THE CORRESPONDING COMPOUNDSHAVING A DOUBLE BOND IN THE 5-POSITION, WHICH COMPRISES OXIDIZING AMEMBER SELECTED FROM THE GROUP CONSISTING OF 3-KETALS OF 18:11-LACTONESOF 11, 20-DIHYDROXY-3-OXO-PREGNANE-18-ACIDS AND THE CORRESPONDINGCOMPOUNDS HAVING A DOUBLE BOND IN THE 5POSITION WITH A COMPOUND OFHEXAVALENT CHROMIUM IN ACID SOLUTION.